EP3303316B1 - Ethynyl derivatives - Google Patents

Ethynyl derivatives Download PDF

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EP3303316B1
EP3303316B1 EP16727661.7A EP16727661A EP3303316B1 EP 3303316 B1 EP3303316 B1 EP 3303316B1 EP 16727661 A EP16727661 A EP 16727661A EP 3303316 B1 EP3303316 B1 EP 3303316B1
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Prior art keywords
methyl
heptan
pyridin
formula
diazabicyclo
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German (de)
English (en)
French (fr)
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EP3303316A1 (en
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Georg Jaeschke
Lothar Lindemann
Antonio Ricci
Eric Vieira
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Priority to RS20200456A priority Critical patent/RS60199B1/sr
Priority to PL16727661T priority patent/PL3303316T3/pl
Priority to SI201630723T priority patent/SI3303316T1/sl
Publication of EP3303316A1 publication Critical patent/EP3303316A1/en
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61P25/16—Anti-Parkinson drugs
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
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Definitions

  • the present invention relates to ethynyl derivatives of formula I wherein
  • NAM metabotropic glutamate receptor antagonists
  • Compounds with a similar main core have been generically described as positive allosteric modulators of the mGluR5 receptor.
  • highly potent mGluR5 antagonists were obtained instead of mGluR5 positive allosteric modulators, which have a completely opposite pharmacology if compared with positive allosteric modulators.
  • a mGluR5 positive allosteric modulator leads to increased receptor activity (Ca 2+ mobilization) in presence of a fixed concentration of glutamate, whereas an allosteric antagonist (negative allosteric modulator, NAM) leads to a reduction of receptor activation.
  • Compounds of formula I are distinguished by having valuable therapeutic properties. They can be used in the treatment of anxiety and pain, depression, Fragile-X syndrom, autism spectrum disorders, Parkinson's disease, and gastroesophageal reflux disease (GERD).
  • the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuro-receptor.
  • Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system (CNS) functions.
  • the glutamate-dependent stimulus receptors are divided into two main groups.
  • the first main group namely the ionotropic receptors, forms ligand-controlled ion channels.
  • the metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein coupled receptors.
  • these eight receptors can be sub-divided into three sub-groups: mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
  • Negative allosteric modulators of metabotropic glutamate receptors belonging to the first group, can be used for the treatment or prevention of acute and/or chronic neurological disorders such as Parkinson's disease, Fragile-X syndrome, autistic disorders, cognitive disorders and memory deficits, as well as chronic and acute pain and gastro-esophageal reflux disease (GERD).
  • acute and/or chronic neurological disorders such as Parkinson's disease, Fragile-X syndrome, autistic disorders, cognitive disorders and memory deficits, as well as chronic and acute pain and gastro-esophageal reflux disease (GERD).
  • GSD gastro-esophageal reflux disease
  • treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia.
  • Further treatable indications are ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions.
  • ALS amyotrophic lateral sclerosis
  • mGluR5 disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain and drug dependency ( Expert Opin. Ther. Patents (2002), 12, (12 )).
  • WO02/062323 discloses the use of mGlu5 receptor antagonists for the treatment of pruritic conditions. Alagille et al. (Bioorg. Med. Chem. Lett.
  • WO2014/060384 discloses ethynyl derivatives which are mGluR5 antagonsits useful for the treatment of anxiety, pain, depression, Fragile-X syndrome, autism spectrum disorders, Parkinson's disease and gastroesophageal reflux disease.
  • Selective mGluR5 antagonists are especially useful for the treatment of disorders where reduction of mGluR5 receptor activation is desired, such as anxiety and pain, depression, Fragile-X syndrome, autism spectrum disorders, Parkinson's disease, and gastro esophageal reflux disease (GERD)
  • Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts, the above-mentioned compounds as pharmaceutically active substances and their production.
  • Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts, the above-mentioned compounds as pharmaceutically active substances and their production.
  • medicaments based on a compound in accordance with the invention and their manufacture as well as the use of the compounds in the control or prevention of mGluR5 receptor (NAM) mediated disorders which are anxiety and pain, depression, Fragile-X syndrome, autism spectrum disorders, Parkinson's disease, and gastro-esophageal reflux disease (GERD, and, respectively, for the production of corresponding medicaments.
  • NAM mGluR5 receptor
  • FIG. 1 The main difference between positive- and negative allosteric modulators can be seen in figure 1 .
  • An mGluR5 positive allosteric modulator (PAM) leads to increased receptor activity (Ca 2+ mobilisation) in presence of a fixed concentration of glutamate whereas an allosteric antagonist (negative allosteric modulator, NAM) leads to a reduction of receptor activation.
  • a monoclonal HEK-293 cell line stably transfected with a cDNA encoding for the human mGlu5a receptor was generated; for the work with mGlu5 Positive Allosteric Modulators (PAMs), a cell line with low receptor expression levels and low constitutive receptor activity was selected to allow the differentiation of agonistic versus PAM activity.
  • PAMs mGlu5 Positive Allosteric Modulators
  • Cells were cultured according to standard protocols (Freshney, 2000) in Dulbecco's Modified Eagle Medium with high glucose supplemented with 1 mM glutamine, 10% (vol/vol) heat-inactivated bovine calf serum, Penicillin/Streptomycin, 50 ⁇ g/ml hygromycin and 15 ⁇ g/ml blasticidin (all cell culture reagents and antibiotics from Invitrogen, Basel, Switzerland). About 24 hrs before an experiment, 5x10 4 cells/well were seeded in poly-D-lysine coated, black/clear-bottomed 96-well plates.
  • the cells were loaded with 2.5 ⁇ M Fluo-4AM in loading buffer (1xHBSS, 20 mM HEPES) for 1 hr at 37°C and washed five times with loading buffer.
  • the cells were transferred into a Functional Drug Screening System 7000 (Hamamatsu, Paris, France), and 11 half logarithmic serial dilutions of test compound at 37°C were added and the cells were incubated for 10-30 min with on-line recording of fluorescence.
  • the agonist L-glutamate was added to the cells at a concentration corresponding to EC 20 (typically around 80 ⁇ M) with on-line recording of fluorescence; in order to account for day-to-day variations in the responsiveness of cells, the EC 20 of glutamate was determined immediately ahead of each experiment by recording of a full dose-response curve of glutamate.
  • cDNA encoding human mGlu 5a receptor was transiently transfected into EBNA cells using a procedure described by Schlaeger and Christensen [Cytotechnology 15:1-13 (1998 )].
  • Cell membrane homogenates were stored at -80°C until the day of assay where upon they were thawed and resuspended and polytronised in 15 mM Tris-HCl, 120 mM NaCl, 100 mM KCl, 25 mM CaCl 2 , 25 mM MgCl 2 binding buffer at pH 7.4 to a final assay concentration of 20 ⁇ g protein/ well.
  • membranes were filtered onto unifilter (96-well white microplate with bonded GF/C filter preincubated 1 h in 0.1% PEI in wash buffer, Packard BioScience, Meriden, CT) with a Filtermate 96 harvester (Packard BioScience) and washed 3 times with cold 50 mM Tris-HCl, pH 7.4 buffer. Nonspecific binding was measured in the presence of 10 ⁇ M MPEP. The radioactivity on the filter was counted (3 min) on a Packard Top-count microplate scintillation counter with quenching correction after addition of 45 ⁇ l of microscint 40 (Canberra Packard S.A., Zurich, Switzerland) and shaking for 20 min.
  • the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art.
  • the reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.
  • the present compounds of formula I and their pharmaceutically acceptable salts may be prepared by methods, known in the art, for example by the process variant described below, which process comprises reacting a compound of formula II wherein X is a halogen atom selected from bromine or iodine with a suitable aryl-acetylene of formula III to form a compound of formula I wherein the substituent R 1 is described above, in enantiomerically pure form with the absolute stereochemistry as drawn in formula I or by using II in racemic form followed by chiral separation of I to yield the optically pure enantiomer; and if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
  • the preparation of compounds of formula I is further described in more detail in schemes 1 to 3 and in examples 1 - 4.
  • a halo-pyridine compound of formula IIa can be obtained by a Palladium catalyzed reaction of an appropriate dihalogenated pyridine such as 2-bromo-5-iodo-pyridine with an appropriately substitued cyclic urea of formula 5 (scheme 1). Reaction of a 2-chloro- or 2-fluoro-pyridine having a bromine or iodine in position 5 with a bicyclic urea of formula 5 can also form a compound of formula IIa by an aromatic nuclophilic substitution reaction using basic conditions such as for example NaH/THF or Cesium carbonate/DMF.
  • the compound of formula 5 can be obtained starting from an appropriately protected 2-amino-1-carboxylic acid of formula 1 which can be obtained using procedures similar to those described by Gorrea & al., Tetrahedron asymmetry, 21, 339(2010 ).
  • the acid function of 1 is transformed via an acylazide intermediate into the corresponding isocyanate 2 (Curtius rearrangement) which then cyclizes to form the bicyclic urea compound 3.
  • the free NH group of 3 can be methylated according to standard procedures to form compound 4 which is then deprotected to yield the cyclic urea 5.
  • optically pure intermediates 2 to 5 starting from an optically pure protected acid of formula 1 or by separation of the racemic mixture at any stage of the synthesis using 'procedures known to persons skilled in the art.
  • R 1 in this scheme means phenyl substituted by (R 1 ) n .
  • W is either hydrogen or an in-situ cleavable protecting group such as a trialkylsilyl- or aryldialkylsilyl-group, preferably hydrogen or trimethylsilyl
  • Another possibility consists of reacting IIa with trimethylsilyl acetylene to yield a compound of formula Ia where R 1 is trimethylsilyl and then do a second Sonogashira reaction with an appropriate aryl bromide or aryl iodide to yield a compound of formula I (scheme not shown).
  • the enantiomers can be separated at any given stage during the synthesis of compounds of formula I using procedures known to persons skilled in the art.
  • R 1 in this scheme means phenyl substituted by (R 1 ) n .
  • Pharmaceutically acceptable salts of compounds of formula I can be manufactured readily according to methods known per se and taking into consideration the nature of the compound to be converted into a salt.
  • Inorganic or organic acids such as, for example, hydrochloric acid, hydro-bromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane sulphonic acid, p-toluene sulphonic acid are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I.
  • Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calcium, magnesium, basic amines or basic amino acids are suitable for the formation of pharmaceutically acceptable salts of acidic compounds.
  • the compounds of formula I and their pharmaceutically acceptable salts are, as already mentioned above, metabotropic glutamate receptor antagonists and can be for use in the treatment or prevention of mGluR5 receptor mediated disorders, such as acute and/or chronic neurological disorders, cognitive disorders and memory deficits, as well as acute and chronic pain.
  • Treatable neurological disorders are for instance epilepsy, schizophrenia, anxiety, acute, traumatic or chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Huntington's chorea, ALS, multiple sclerosis, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficient functions, such as e.g.
  • treatable indications are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia.
  • Treatable kinds of pain include inflammatory pain such as arthritis and rheumatoid disease, vasculitis, neuropathic pain such as trigeminal or herpetic neuralgia, diabetic neuropathy pain, causalgia, hyperalgesia, severe chronic pain, post-operative pain and pain associated with various conditions like cancer, angina, renal or billiay colic, menstruation, migraine and gout.
  • inflammatory pain such as arthritis and rheumatoid disease, vasculitis, neuropathic pain such as trigeminal or herpetic neuralgia, diabetic neuropathy pain, causalgia, hyperalgesia, severe chronic pain, post-operative pain and pain associated with various conditions like cancer, angina, renal or billiay colic, menstruation, migraine and gout.
  • the inhibition (antagonists) curves were fitted with a four parameter logistic equation giving IC 50 , and Hill coefficient using the iterative non-linear curve fitting software Origin (Microcal Software Inc., Northampton, MA, USA).
  • the Ki values of the compounds tested are given.
  • the compounds of the present invention are mGluR 5a receptor antagonists.
  • the activities of compounds of formula I as measured in the assay described above are in the range of K i ⁇ 100 ⁇ M.
  • the compounds of formula I and pharmaceutically acceptable salts thereof can be for use as medicaments, e.g. in the form of pharmaceutical preparations.
  • the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
  • the compounds of formula I and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations.
  • Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatine capsules.
  • Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose.
  • Adjuvants such as alcohols, polyols, glycerol, vegetable oils, can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols.
  • the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • medicaments containing a compound of formula I or pharmaceutically acceptable salts thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
  • the dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case.
  • the effective dosage for oral or parenteral administration is between 0.01-10 mg/kg/day, with a dosage of 0.1-5 mg/ kg/day being preferred for all of the indications described.
  • Step 1 (rac)-(1SR,2RS)-2-(Naphthalen-2-ylmethoxycarbonylamino)cyclobutanecarboxylic acid methyl ester:
  • Step 2 (rac)-(1SR,2RS)-2-(Naphthalen-2-ylmethoxycarbonylamino)cyclobutanecarboxylic acid
  • Step 3 (rac)-(1RS,5SR)-3-Oxo-2,4-diaza-bicyclo[3.2.0]heptane-2-carboxylic acid naphthalen-2-ylmethyl ester
  • Step 4 (rac)-(1RS,5SR)-4-Methyl-3-oxo-2,4-diaza-bicyclo[3.2.0]heptane-2-carboxylic acid naphthalen-2-ylmethyl ester
  • Step 5 (rac)-(1SR,5RS)-2-Methyl-2,4-diaza-bicyclo[3.2.0]heptan-3-one
  • Step 6 (rac)-(1RS,5SR)-2-(5-Iodo-pyridin-2-yl)-4-methyl-2,4-diazabicyclo[3.2.0]heptan-3-one
  • Step 7 (rac)-(+/-)-(1SR,5RS)-2-Methyl-4-(5-(phenylethynyl)pyridin-2-yl)-2,4-diazabicyclo[3.2.0]heptan-3-one
  • Ethynylbenzene (73 ⁇ l, 68 mg, 0.67 mmol), Bis(triphenylphosphine)palladium(II) chloride (14 mg, 20 ⁇ mol), copper (I) iodide (1.9 mg, 10.0 ⁇ mol), Triphenylphosphine (1.8 mg, 7.7 ⁇ mol) and 107 ⁇ l of Triethylamine (101 mg, 140 ⁇ l, 1.0 mmol) were added.
  • the dark brown solution was stirred 3h at 60°C. The reaction was worked up with ethyl acetate/water, dried and concentrated in vaccuo.
  • Step 8 (-)-(1S,5R)-2-Methyl-4-(5-(phenylethynyl)pyridin-2-yl)-2,4-diazabicyclo[3.2.0]heptan-3-one and (+)-(1R,5S)-2-methyl-4-(5-(phenylethynyl)pyridin-2-yl)-2,4-diazabicyclo[3.2.0]heptan-3-one
  • Peak detection was realized using a UV-detector as well as an optical rotation detector (ORD) where one peak has a negative signal (the (-)-enantiomer), and the other peak has a positive signal (the (+)-enantiomer).
  • ORD optical rotation detector
  • Tablets of the following composition are produced in a conventional manner: mg/Tablet Active ingredient 100 Powdered. lactose 95 White corn starch 35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10 Magnesium stearate 2 Tablet weight 250
  • Tablets of the following composition are produced in a conventional manner: mg/Tablet Active ingredient 200 Powdered. lactose 100 White corn starch 64 Polyvinylpyrrolidone 12 Na carboxymethylstarch 20 Magnesium stearate 4 Tablet weight 400
  • Capsules of the following composition are produced: mg/Capsule Active ingredient 50 Crystalline. lactose 60 Microcrystalline cellulose 34 Talc 5 Magnesium stearate 1 Capsule fill weight 150
  • the active ingredient having a suitable particle size, the crystalline lactose and the microcrystalline cellulose are homogeneously mixed with one another, sieved and thereafter talc and magnesium stearate are admixed.
  • the final mixture is filled into hard gelatine capsules of suitable size.

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RS20200456A RS60199B1 (sr) 2015-06-03 2016-05-31 Derivati etinila
PL16727661T PL3303316T3 (pl) 2015-06-03 2016-05-31 Pochodne etynylu
SI201630723T SI3303316T1 (sl) 2015-06-03 2016-05-31 Derivati etinila
HRP20200638TT HRP20200638T1 (hr) 2015-06-03 2020-04-22 Derivati etinila

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US11059766B2 (en) 2021-07-13
HRP20200638T1 (hr) 2020-07-10
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US20210300844A1 (en) 2021-09-30
UA120309C2 (uk) 2019-11-11
AR104842A1 (es) 2017-08-16
CN107849006B (zh) 2020-11-13
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